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This article reviews the use of modafinil in palliative care, and its use in promoting vigilance and wakefulness. Modafinil's therapeutic and chemical class, mechanism of action, pharmacokinetics, indications, dosage, side effects, and drug interactions are also discussed. Modafinil seems to fit the requirements of portmanteau, using one drug to treat multiple symptoms.
Charcot-Marie-Tooth disease, the most common hereditary motor and sensory neuropathy, is a slowly progressive disorder characterized by diffuse muscle weakness and prominent distal atrophy that predominantly involves the intrinsic muscles of the feet and the peroneal muscles. It results in marked reduction in functional aerobic capacity during exercise and fatigue is commonly reported. To date, no pharmacologic treatment has been shown to be effective for treating fatigue in Charcot-Marie-Tooth. Modafinil is used to treat the symptoms of fatigue and excessive daytime sleepiness in narcolepsy. However, fatigue and subsequent excessive daytime sleepiness secondary to fatigue are common symptoms in many neurologic disorders. Prior reports on patients with myotonic muscular dystrophy, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis, have shown beneficial effects of modafinil in treating fatigue. We report 4 patients with genetically confirmed Charcot-Marie-Tooth disease who had significant fatigue that was almost completely relieved by modafinil.
PURPOSE: The purpose of this study was to investigate the effect of acute ingestion of modafinil (M) on time to exhaustion during high-intensity exercise. Modafinil (M) is a psychostimulant developed to treat narcolepsy, with "arousal" properties attributed to an increased release of dopamine in the CNS. Because other stimulants with similar properties have ergogenic effects, it was hypothesized that acute treatment with M would enhance physical performance. METHODS: Fifteen healthy male subjects, with a maximal aerobic power (VO2max) of 47 +/- SD 8 mL x kg x min, exercised on a cycle ergometer for 5 min at 50% VO2max and then at approximately 85% VO2max to exhaustion. They did this weekly for 3 wk: a control trial (C) the first week, and then 3 h after ingesting either placebo (P) or M (4 mg x kg) during the remaining 2 wk. The P and M trials were conducted with a balanced order, double-blind design. RESULTS: : Mean +/- SD times to exhaustion at 85% VO2max (TE) were 14.3 +/- 2.8, 15.6 +/- 3.8 and 18.3 +/- 3.5 min for the C, P, and M trials, respectively. TE for M was significantly longer than for the C and P trials. Oxygen uptake at exhaustion was slightly but significantly greater for M compared with P and C. HR increased with time and was further elevated by M. Subjective ratings of perceived exertion (RPE) were significantly lower for M compared with C and P but only after 10 min of exercise at 85% VO2max. CONCLUSION: Acute ingestion of modafinil prolonged exercise time to exhaustion at 85% VO2max and reduced RPE. The RPE results suggest that the dampening of the sensation of fatigue was likely a factor responsible for the enhanced performance.
BACKGROUND: Fatigue is widespread among human immunodeficiency virus-positive (HIV+) patients, yet few studies have assessed effective treatments. The authors conducted a pilot study to evaluate the efficacy of modafinil for fatigue in this clinical population. METHOD: Response was evaluated after a 4-week open-label trial. Data were collected from February 2003 through January 2004. Responders were offered 8 additional weeks of modafinil. Inclusion criteria included written approval from the primary care physician, clinically significant fatigue, current use of anti-retroviral medications, and the absence of treatable medical conditions known to cause fatigue. Exclusion criteria included untreated major depression and current substance abuse. Major outcome measures were the Fatigue Severity Scale, Chalder Fatigue Scale, Hamilton Rating Scale for Depression, Beck Depression Inventory, and neuropsychological tests assessing verbal memory, speed of processing, and executive function. Immunologic and virologic measures were performed at baseline and week 4 to assess safety of treatment. RESULTS: All 30 patients who enrolled completed 4 weeks of treatment; 24 (80%) were rated as responders. Responders showed statistically significant improvement on all measures of fatigue, depressive symptoms, and executive function, while nonresponders did not. Mean values of CD4 cell count and HIV RNA viral load did not change. The most common side effect was headache, followed by irritability and feeling "hyper." CONCLUSION: This pilot study shows encouraging results for modafinil in alleviation of fatigue in HIV+ patients. In addition, depressive symptoms were substantially reduced. Improvements on measures of verbal memory and executive function were significant, but in the absence of a placebo control, the magnitude of effect due to practice cannot be determined.
Fatigue is a symptom that is frequently found in chronic pain patients with low back pain and/or neck pain. At the present time, no specific psychopharmacological treatment for this problem has been identified. Modafinil is a wakefulness-promoting agent that the FDA has approved for the treatment of excessive daytime sleepiness associated with narcolepsy. There have been reports on the use of modafinil for the treatment of fatigue in various neurological syndromes. This literature is reviewed. As such, modafinil treatment was initiated for a patient with severe fatigue associated with chronic low back pain and neck pain. There was dramatic improvement in fatigue and associated function. This case is described. It is the first such case report in the literature. The significance of this finding to the treatment of pain-associated fatigue is discussed.
OBJECTIVE: To investigate the effect of diazepam and modafinil on acute hepatic failure in mice. METHODS: Acute liver failure was induced in male Kunming strain mice by enterocoelia injecting the mice with D-GalN and LPS . The mice in the treatment groups were given corresponding drug 2 h before the administration of D-GalN and LPS, and the mice in the control group were given the same dose of distilled water. The 24-hour survival rate, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were compared. Serum levels of TNF-alpha and IL-1 and the levels of SOD, MDA, GR, GSH, NO and NOS in the liver were determined. RESULTS: Treatment with diazepam increased the survival rate and improved liver histological feature. Diazepam inhibited the serum levels of ALT, AST, TNF-alpha and IL-1, and reduced levels of MDA, NO and NOS and increased levels of GR and SOD in the liver. Modafinil decreased liver histological feature, increased the serum levels of ALT, AST, TNF-alpha and IL-1, increased level of MDA, and inhabited levels of SOD and GR in the liver. CONCLUSION: Treatment with diazepam may suppress the D-GalN/LPS-induced acute hepatic failure and modafinil may facilitate the acute hepatic failure.
Treatment-resistant depression, i.e. partial or non response to antidepressants in spite of various treatment attempts with optimized doses and combinations, is rather common. With residual symptoms such as tiredness, anhedonia and concentration disturbances, the treatment strategy has often been to use monoamino-oxidase inhibitors (MAOIs). Their use, however, is limited due to interaction problems. Modafinil is recently developed wake-promoting drug with only minor side-effects. Pilot studies indicate that it appears to have an augmentation effect in treatment-resistant depression. This open-label study performed in the private psychiatric practice setting is the first to make a comprehensive evaluation of the target patient profile based on patient-reported symptoms. Modafinil in doses of 100-400 mg was administered as augmentation to ongoing antidepressant therapy in patients with partial response and suffering from hypersomnia. The total number of patients was 21 and 43% of these were responders (i.e. had a score reduction of >50% on the Major Depression Inventory (MDI) as well as remitters, i.e. the remission rate was 43%. At endpoint, the responders had psychological distress scores on the Symptom Checklist (SCL-92) on the level of the general Danish population. Baseline characteristics for responders were lower scores on depression, hostility, anxiety, somatization, obsession and psychoticism. Modafinil thus appears to be an appropriate augmentation to antidepressant treatment, leading to a remission rate of 43%. However, the results from this open-label study need ot be confirmed in a placebo-controlled trial.
Modafinil, a novel stimulant which has several remarkable features that distinguish it from other stimulants, has been developed by Lafon, a French pharmaceutical company. Unlike the amphetamines, for example, modafinil is reported to have minimal peripheral side effects at therapeutic doses. It also appears to have a low abuse potential, does not interfere with normal sleep, and does not seem to produce tolerance. It improves vigilance especially in sleep-deprived subjects. It has been used clinically for up to 3 years in the treatment of narcolepsy and idiopathic hypersomnia. It could be an ideal replacement for amphetamine in short-term operations in which fatigue might threaten the successful completion of a mission. We recommend that military laboratories experienced in studying sustained performance include modafinil or perhaps a more selective alpha 1 receptor agonist in their investigations.
Modafinil is a psychostimulant compound that is just now becoming available in many countries for treatment of narcoleptic and hypersomnic patients. Whereas sleep attacks and drowsiness can be effectively improved, the drug does not sufficiently reduce cataplectic seizures. It therefore is often used in combination with tricyclic antidepressant medication, although little is known about the possible interactions. This case report describes a narcoleptic patient chronically treated with clomipramine who started receiving modafinil. The blood concentrations of clomipramine and its metabolite showed a significant dose-dependent and reversible increase under modafinil. Since the patient was genotypically and phenotypically a cytochrome P450 2D6 poor metabolizer, the authors attribute the relevant pharmacokinetic interaction to another clomipramine-metabolizing enzyme.
Polysomnograms were obtained from 37 volunteers, before (baseline) and after (two consecutive recovery nights) a 64-h sleep deprivation, with (d-amphetamine or modafinil) or without (placebo) alerting substances. The drugs were administered at 23.00 hours during the first sleep deprivation night (after 17.5 h of wakefulness), to determine whether decrements in cognitive performance would be prevented; at 05.30 hours during the second night of sleep deprivation (after 47.5 h of wakefulness), to see whether performance would be restored; and at 15.30 hours during the third day of continuous work, to study effects on recovery sleep. The second recovery night served to verify whether drug-induced sleep disturbances on the first recovery night would carry over to a second night of sleep. Recovery sleep for the placebo group was as expected: the debt in slow-wave sleep (SWS) and REM sleep was paid back during the first recovery night, the rebound in SWS occurring mainly during the first half of the night, and that of REM sleep being distributed evenly across REM sleep episodes. Recovery sleep for the amphetamine group was also consistent with previously published work: increased sleep latency and intrasleep wakefulness, decreased total sleep time and sleep efficiency, alterations in stage shifts, Stage 1, Stage 2 and SWS, and decreased REM sleep with a longer REM sleep latency. For this group, REM sleep rebound was observed only during the second recovery night. Results for the modafinil group exhibited decreased time in bed and sleep period time, suggesting a reduced requirement for recovery sleep than for the other two groups. This group showed fewer disturbances during the first recovery night than the amphetamine group. In particular, there was no REM sleep deficit, with longer REM sleep episodes and a shorter REM latency, and the REM sleep rebound was limited to the first REM sleep episode. The difference with the amphetamine group was also marked by less NREM sleep and Stage 2 and more SWS episodes. No REM sleep rebound occurred during the second recovery night, which barely differed from placebo. Hence, modafinil allowed for sleep to occur, displayed sleep patterns close to that of the placebo group, and decreased the need for a long recovery sleep usually taken to compensate for the lost sleep due to total sleep deprivation.
Modafinil is a selective wakefulness-promoting agent with beneficial effects in narcolepsy and conditions of sleep deprivation. In a double-blind study we examined its effects in 30 healthy, non sleep-deprived students (19 men and 11 women, aged 19-23 years), who were randomly allocated to placebo, 100 or 200 mg modafinil and 3 h later completed 100 mm visual analogue scales relating to mood and bodily symptoms, before and after an extensive battery of cognitive tests (pen and paper and CANTAB). There were no significant differences between the three treatment groups on any of the cognitive tests used in this study. There was a significant post-treatment change in the factor measuring 'somatic anxiety' and in individual ratings of 'shaking', 'palpitations', 'dizziness', 'restlessness', 'muscular tension', 'physical tiredness' and 'irritability', which was mainly due to significantly higher ratings of somatic anxiety in the 100 mg group compared with the other two groups. Further changes in mood were revealed after the stress of cognitive testing, with the 100 mg group showing greater increases in the 'psychological anxiety' and the 'aggressive mood' factors (as measured from the Bond and Lader scales).
1. Modafinil, a putative central alpha 1 adrenergic agonist, was tested in idiopathic hypersomnia and narcolepsy. 2. Sleep attacks and drowsiness were significantly decreased in 83% of 18 hypersomniac subjects and 71% of 24 narcoleptics. 3. When cataplectic episodes were not totally suppressed the association of a low dose of Clomipramine was successful in improving them. 4. Modafinil, used for at least 3 years in some patients, produces, in most cases, no peripheric sides effects, does not disturb night sleep and is never responsible of tolerance of drug dependence.
Modafinil did not affect spontaneous and K(+)-evoked [3H]5-HT efflux from cortical synaptosomes while it increased K(+)-evoked tritium efflux from cortical slices, an action that became stronger in the presence of paroxetine. In contrast, DL-fenfluramine and fluoxetine were able to enhance spontaneous and/or K(+)-evoked tritium efflux from synaptosomes and slices. These results suggest that modafinil does not affect 5-HT transmission from cortical synaptosomes and that its 5-HT releasing action is different from that of DL-fenfluramine and fluoxetine.
Enantiomers of modafinil, (diphenylmethyl)sulphinyl-2-acetamide, were separated by an amylose tris[(S)-1-phenylethylcarbamate] chiral stationary phase, using acetonitrile: water (25:75 v/v) as mobile phase, with excellent selectivity (alpha=1.4) and resolution factors (R(s)=1.5). The assay involved a solid-phase extraction of the enantiomers of modafinil from plasma using a C(18) Cartridge. A good linear relationship was obtained in the concentration of 0.15-3 microg ml(-1) for each enantiomer. The method developed is sufficiently accurate and precise to be used for clinical samples and has a good selectivity with the two main circulating metabolites: the (diphenylmethyl)sulphinyl-2-acetic acid and (diphenylmethyl)sulphonyl-2-acetamide. The use of a polysaccharide-based column on multimodal elution was explored in developing the method.
PRIMARY OBJECTIVE: This case report reviews the history and post-operative status of a 77-year-old woman who underwent transcallosal resection of an intra-ventricular haemorrhagic subependymoma and who remained in a deep post-operative state of lethargy and listlessness. MAIN OUTCOME MEASURES: Glasgow Coma Scale (GCS) and detailed clinical observations. RESULTS: The patient (GCS=8) was initiated on methylphenidate 20 mg per day on the 6th day after surgery, but treatment was discontinued 2 days later due to elevated blood pressure and persistent tachycardia. Pemoline 37.5 mg per day was initiated, but treatment was stopped after 3 days due to lack of response. Treatment with modafinil 400 mg per day was initiated on the 11th day after surgery and the patient's consciousness level rapidly improved on the 14th day. On the 16th day after surgery, she was completely alert (GCS=15). CONCLUSIONS: Modafinil appeared to be beneficial for improving wakefulness and responsiveness in a patient with central nervous system trauma in the post-operative state.
The efficacy of modafinil, a psychostimulant drug acting on postsynaptic alpha-1 adrenergic receptors, as a treatment for excessive daytime sleepiness was studied in 123 patients. Subjects included 94 narcoleptic patients (76 with cataplexy), 23 hypersomnia patients and 6 patients with disrupted nocturnal sleep (DNS) and excessive daytime sleepiness (EDS). Clinical efficacy of the treatment on each symptom (EDS, cataplexy and DNS) was evaluated on a four-point scale from excellent to absent. The effectiveness of modafinil as a treatment for EDS was excellent in 17% of all patients, good in 63%, fair in 17% and absent in 3%. The incidence of side effects was rather low (14 of 123 patients) and most of them disappeared (11 patients) when doses were reduced.
STUDY OBJECTIVES: Sleep loss consistently impairs performance on measures of alertness, vigilance, and response speed, but its effects on higher-order executive functions are not well delineated. Similarly, whereas deficits in arousal and vigilance can be temporarily countered by the use of several different stimulant medications, it is not clear how these compounds affect complex cognitive processes in sleep-deprived individuals. DESIGN: We evaluated the effects of double-blind administration of 3 stimulant medications or placebo on the ability to appreciate humor in visual (cartoons) or verbal (headlines) stimuli presented on a computer screen following 49.5 hours of sleep deprivation. SETTING: In-residence sleep-laboratory facility at the Walter Reed Army Institute of Research. PARTICIPANTS: Fifty-four healthy adults (29 men, 24 women), ranging in age from 18 to 36 years. INTERVENTIONS: Each participant was randomly assigned to 1 of 3 stimulant medication groups, including caffeine, 600 mg, n = 12; modafinil, 400 mg, n = 11; dextroamphetamine, 20 mg, n = 16; or placebo, n = 14. MEASUREMENTS AND RESULTS: Humor appreciation for cartoon stimuli was enhanced by modafinil relative to both placebo and caffeine, but there was no effect of any stimulant medication on the appreciation of verbal humor during sleep loss. In contrast, all 3 stimulants improved psychomotor response speed, whereas only caffeine and dextroamphetamine improved ratings of subjective sleepiness. CONCLUSIONS: Findings suggest that, despite similar alerting and vigilance-promoting effects, these 3 compounds have significantly different effects on those highly complex cognitive abilities mediated by the pre-frontal cortex.
Avolition affects quality of life in chronic schizophrenia. We investigated the effect of modafinil upon unconstrained motor activity in 18 male patients. In a randomised crossover design study, wrist-worn actigraphic monitors were used to objectively record motor activity over a 20 h period. Patients' total activity was significantly greater when given the drug. These data suggest that modafinil increases quantifiable motor behaviour in schizophrenia and may have an impact on avolition.